Gels formed by biocompatible materials have many applications in medicine and industry, but have been limited by the need for high molecular weight compounds, high concentrations of polymer, or organic solvents to form the gels. It would be desirable to synthesize gels that form in aqueous solutions at low concentrations of simple polymers.
A gel consists of continuous networks of molecular aggregates in which solvent molecules are trapped. The gel phase requires stereochemical correspondence between these small molecules in order to generate cohesion. Low molecular weight molecules that form macroscopic gels may do so by a variety of microscopic packings including linear aggregates, micelles, and other structures. Components responsible for the mechanical elasticity of gels may be joined by fragile non-covalent bonds, yielding materials with mechanical properties suitable for pastes or spreads with many cosmetic or therapeutic applications.
High molecular weight network systems are also well described which form gels in water, such as gelatin and starch. These gels form when the macromolecules are mixed with water, heated, and cooled.
There are several examples of low molecular weight compounds that form gels, but predominantly in toxic organic solvents. The chemical structures of such compounds are varied, including for example, organic acids with long aliphatic chains, partially fluorinated n-alkanes, cholesterol derivatives, oxyanthracene derivatives, and others as discussed by Hanabusa, K., et al., J. Chem. Soc. Chem. Commun. 4, 390-392 (1993).
Among the low molecular weight compounds that form gels are amino acids and peptide derivatives. Already described in patents to Saito T., et al., Jp. 50022801 (1975) and Saito T., et al., U.S. Pat. No. 3,969,087 (1976) are the structures of amino acid esters and amides containing fatty acids and higher alcohols which form gels in oils and other organic solvents.
Hanabusa K., et al., J. Chem. Soc., Chem. Commun. (18)1371-1373 (1992) discloses that the alanine derivative N-benzyl-oxycarbonyl L-alanine 4-hexadecanoyl-2nitrophenyl ester forms thermally reversible gels in methanol and cyclohexane at concentrations below 1%. Similarly, Hanabusa, K., et al., J. Chem. Soc., Chem. Commun. 4, 390-392 (1993) discloses that N-benzyloxycarbonyl L-valyl-valine n-octadecylamide makes gels in several organic liquids.
Depsipeptides with the formulas (X--X.sup.1 --OCH.sub.2 CH.sub.2 COO).sub.n where X and X.sup.1 can be valine or isoleucine derivatives form thermostable gels with such solvents as methylene chloride, acetonitrile, ethylacetate, and acetone as discussed in De Vries E. J., et al., J. Chem. Soc., Chem. Commun. (3) 238-240 (1993).
Ihara H., et al., J. Chem. Soc., Chem. Commun. (17) 1244-1245 (1992) relates to benzyl-oxycarbonyl .beta.-alanine glumamate derivatives in which both carboxyl groups are derivitized with N-dodecylamide groups, dissolve in hot benzene, but on cooling these mixtures form gels. Notably less common are low molecular weight compounds that form gels in water. Among these is the synthetic glycolipid N-octyl-D-gluconamide, which upon prolonged heating in water solutions partly hydrolyses.
It is also noted that t-butoxycarbonyl-valyl-valylisoleucine methylester forms micelles in chloroform in Jayakumar A., et al., J. Chem Soc., Chem. Commun. (10) 853-855 (1993). The critical micelle concentration of this peptide is 2.5 mM.
Kalopissis G., et al., French Patent 1,397,231 (1965) discloses asparagine derivatives whose amino groups are acylated by fatty acids and whose amide groups are alkylated. These derivatives form gels in water at concentrations around 3%.
Mandal, A. B. and Jayakumar, J., J. Chem. Soc., Chem. Commun. 3, 237-238 (1993) has shown that the tetrapeptide Tyr-Gly-Phe-Ala benzylester diluted in trifluoroacetate/water mixtures forms micelles. While Weitzberg M., et al., PCT Int. Appl. 90 15,602 (1990) and Burch R. M., et al., Proc Natl. Acad. Sci., USA, 88 (2) 355-359 (1991) show that some 9-fluorenylmethoxycarbonyl-(Fmoc-) amino acid derivatives modulate the immune response, Noronha-Blob L., et al., Eur. J. Pharmacol., 199(3) 387-388 (1991) has also shown these derivatives have potential to reduce endotoxic shock.
Notably absent from current gel-forming systems is the ability to rapidly and inexpensively form gels from low molecular weight compounds at low concentrations that are stable in aqueous, non-toxic solutions. Such gels would have many applications in medicine and industry.